Recent findings make it clear that there is no true "latency phase" associated with HIV disease, at least in the strict sense of the term. Active virus replication is ongoing throughout the long clinical asymptomatic period which typically follows initial infection. These findings make it likely that the virus itself plays a key role in the clinical deterioration of the infected individual. Both in vitro and in vivo data demonstrate the ability of tissue macrophages to be infected by and harbor HIV. These cells may serve both as long-lived mobile reservoirs for spreading the virus and as the mediators of some of the major clinical syndromes associated with advanced HIV disease. There has been considerable speculation that they play a pivotal role in the pathogenesis of AIDS, although relatively little is understood regarding their role in the development of AIDS-associated opportunistic infections. In the unique environment of the lung, where alveolar macrophages represent the principal mediators of the host cell immune response against lung pathogens, the influence of HIV infected cells upon pulmonary defense systems is particularly pertinent. The overall objective of this research program is to delineate the mechanisms by which HIV infection of alveolar macrophages contributes to the pulmonary dysfunction that ultimately results in opportunistic infections. These mechanisms encompass both the effects of HIV upon the functioning of the alveolar macrophage, and interactions between HIV and other pathogens found in the immunocompromised lung. With regard to the alveolar macrophage itself, this project is specifically oriented towards understanding the dysregulation of cytokine production in alveolar macrophages resulting from HIV infection and its pathophysiological consequences. Within this project, we will also address the role of CMV, the other virus most commonly associated with AIDS in impairing lung defense mechanisms. Aspects of alveolar macrophage function with respect to infection by P. carinii and mycobacteria will be also investigated within the context of collaborative projects in the program. Our aim is to develop data on the operative dynamics within the pulmonary system of HIV infected individuals, both between different invading organisms and between those organisms and the host tissue, in sufficient molecular detail to then pursue specific strategies designed to interfere with these destructive processes. One specific strategy for intervention is presented which utilizes gene therapy as an outgrowth of the reagents and knowledge base generated in this project.